Lipoprotein Interactions in the Vessel Wall
血管壁中脂蛋白的相互作用
基本信息
- 批准号:10589111
- 负责人:
- 金额:$ 54.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AdolescentAdultAffectAgeAnimal ModelAnimalsArteriesAtherosclerosisBindingBiological AssayCardiovascular DiseasesCardiovascular systemCause of DeathCellsCessation of lifeDataEndothelial CellsEndotheliumEquilibriumEventExhibitsFamilyFunctional disorderFutureHigh Density LipoproteinsHumanIn VitroIndividualK-Series Research Career ProgramsLDL Cholesterol LipoproteinsLipidsLipoprotein BindingLipoproteinsLongevityLow-Density LipoproteinsMediatingMusNon-Insulin-Dependent Diabetes MellitusPatientsPersonsPlasmaPopulationProcessProteinsProteoglycanProteomicsRecombinantsRegulationRoleSR-BI receptorSamplingSeriesSpecimenSurface Plasmon ResonanceTestingTherapeuticVascular EndotheliumWorkYouthatherogenesiscardiovascular disorder riskcardiovascular risk factorcohortextracellularfeasibility testinghigh density lipoprotein receptorhigh riskinsightlipidomicsparticlepeptidomimeticsprematurepreventtranscytosis
项目摘要
PROJECT SUMMARY
There is a critical need to stop atherosclerosis initiation and progression, rather than trying to treat its progression
in an advanced state. It is widely recognized that entry and retention of low density lipoproteins (LDL) are key
steps in atherogenesis. However, our data show high density lipoproteins (HDL) can compete with LDL to bind
SR-BI and HDL can interact with LDL to decrease binding to proteoglycans. With the recent realization that
lipoproteins, both LDL and HDL, exist a series of related but compositionally distinct subpopulations, new
questions have arisen as to how lipoprotein subspeciation may affect these igniting steps of atherosclerosis.
This work builds on data generated under PI Shah’s K award (K23HL118132) showing that 1) HDL and LDL
exist as multiple subspecies, 2) specific HDL subspecies, their amount, composition (lipids, proteins) and
function are altered in the plasma of individuals with type 2 diabetes, and 3) the amount of large HDL subspecies
in plasma are inversely correlated with early markers of cardiovascular risk. This proposal also builds on our
preliminary data that shows HDL modulates both LDL transcytosis and binding to proteoglycans, but this is
disrupted in the context of type 2 diabetes. Our overarching hypothesis that that LDL and HDL subspecies
differentially impact transcytosis and proteoglycan binding and disruption of their balance in type 2 diabetes
contributes to the high risk of cardiovascular disease in this population. Using complementary approaches that
include in-vitro cell based assays with animal models and patient samples in adolescents and adults, we aim to
identify and characterize the LDL and HDL subspecies involved in endothelial cell transcytosis (Aim 1) and
extracellular proteoglycan binding (Aim 2) and to understand the impact of type 2 diabetes on these lipoprotein
subspecies (Aim 3). These results have the potential to inform future therapeutic strategies to use recombinant
particles or mimetic peptides to prevent atherosclerosis initiation. The ability to block atherosclerosis initiation
and progression will benefit both youth and adults, and particularly individuals with type 2 diabetes who are at
increased risk for cardiovascular disease.
项目摘要
目前迫切需要阻止动脉粥样硬化的发生和发展,而不是试图治疗其进展
在一个先进的国家。低密度脂蛋白(LDL)的进入和保留是
动脉粥样硬化形成的步骤。然而,我们的数据显示高密度脂蛋白(HDL)可以与LDL竞争结合,
SR-BI和HDL可以与LDL相互作用以减少与蛋白聚糖的结合。随着最近意识到,
脂蛋白,LDL和HDL,存在一系列相关但组成不同的亚群,新的
已经出现了关于脂蛋白亚种类如何影响动脉粥样硬化的这些引发步骤的问题。
这项工作建立在PI Shah的K奖(K23 HL 118132)产生的数据基础上,显示1)HDL和LDL
作为多个亚种存在,2)特定HDL亚种,其量、组成(脂质、蛋白质)和
2型糖尿病患者血浆中的高密度脂蛋白(HDL)功能改变,以及3)大HDL亚种的量
与心血管风险的早期标志物呈负相关。这一建议还建立在我们的
初步数据显示,HDL调节LDL转胞吞作用和与蛋白聚糖的结合,但这是
在2型糖尿病的背景下被破坏。我们的总体假设是低密度脂蛋白和高密度脂蛋白亚种
2型糖尿病中对转胞吞作用和蛋白聚糖结合的不同影响及其平衡的破坏
导致了这一人群患心血管疾病的高风险。使用互补的方法,
包括在青少年和成人中使用动物模型和患者样本进行的基于体外细胞的测定,我们的目标是
鉴定和表征参与内皮细胞转胞吞作用的LDL和HDL亚种(目的1),
细胞外蛋白聚糖结合(Aim 2),并了解2型糖尿病对这些脂蛋白的影响
亚种(目标3)。这些结果有可能为未来的治疗策略提供信息,
颗粒或模拟肽来预防动脉粥样硬化起始。阻断动脉粥样硬化起始的能力
和进展将有利于青年和成年人,特别是2型糖尿病患者谁是在
增加心血管疾病的风险。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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W Sean Davidson其他文献
シンポジウム3:日本における原発性高脂血症の現状 家族性高コレステロール血症の診断および治療の課題.
研讨会3:日本原发性高脂血症的现状:家族性高胆固醇血症的诊断和治疗问题。
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
Kuniko Okumura-Noji;Toshihiko Usami;Giorgio Cavigiolio;Rong Huang;W Sean Davidson;Shinji Yokoyama;Maki Tsujita.;Yamada M;野原 淳 - 通讯作者:
野原 淳
Characterization of ion-exchange column fractionated human and mouse apoA-I subfractions.
离子交换柱分级分离的人和小鼠 apoA-I 亚组分的表征。
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
Kuniko Okumura-Noji;Toshihiko Usami;Giorgio Cavigiolio;Rong Huang;W Sean Davidson;Shinji Yokoyama;Maki Tsujita. - 通讯作者:
Maki Tsujita.
KCNJ5 mutations in aldosterone- and cortisol secreting adrenal adenomas.
醛固酮和皮质醇分泌性肾上腺腺瘤中的 KCNJ5 突变。
- DOI:
- 发表时间:
2012 - 期刊:
- 影响因子:2
- 作者:
Kuniko Okumura-Noji;Toshihiko Usami;Giorgio Cavigiolio;Rong Huang;W Sean Davidson;Shinji Yokoyama;Maki Tsujita.;Yamada M - 通讯作者:
Yamada M
W Sean Davidson的其他文献
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{{ truncateString('W Sean Davidson', 18)}}的其他基金
The structural basis for cholesterol esterification in human plasma
人血浆中胆固醇酯化的结构基础
- 批准号:
10450679 - 财政年份:2020
- 资助金额:
$ 54.89万 - 项目类别:
The structural basis for cholesterol esterification in human plasma
人血浆中胆固醇酯化的结构基础
- 批准号:
10667541 - 财政年份:2020
- 资助金额:
$ 54.89万 - 项目类别:
The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism
载脂蛋白 A-II 在胆固醇和甘油三酯代谢中作用的分子基础
- 批准号:
10533294 - 财政年份:2020
- 资助金额:
$ 54.89万 - 项目类别:
The structural basis for cholesterol esterification in human plasma
人血浆中胆固醇酯化的结构基础
- 批准号:
10206267 - 财政年份:2020
- 资助金额:
$ 54.89万 - 项目类别:
The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism
载脂蛋白 A-II 在胆固醇和甘油三酯代谢中作用的分子基础
- 批准号:
10096569 - 财政年份:2020
- 资助金额:
$ 54.89万 - 项目类别:
The structural basis for cholesterol esterification in human plasma
人血浆中胆固醇酯化的结构基础
- 批准号:
10028460 - 财政年份:2020
- 资助金额:
$ 54.89万 - 项目类别:
The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism
载脂蛋白 A-II 在胆固醇和甘油三酯代谢中作用的分子基础
- 批准号:
10318588 - 财政年份:2020
- 资助金额:
$ 54.89万 - 项目类别:
Autologous Cardiomyocytes from Masseter Muscles to Repair Myocardial Infarction (MI)
咬肌自体心肌细胞修复心肌梗死 (MI)
- 批准号:
9332765 - 财政年份:2017
- 资助金额:
$ 54.89万 - 项目类别:
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